Chlorphenamine

{{Drugbox

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 443519064

| image = Chlorphenamine.svg

| width = 200

| alt =

| image2 = Chlorpheniramine for veterinary use.jpg

| alt2 =

| tradename = Chlor-Trimeton; Piriton; Chlor-Tripolon; Allergex

| Drugs.com = {{drugs.com|monograph|chlorpheniramine-maleate-tannate-dexchlorpheniramine-maleate}}

| MedlinePlus = a682543

| pregnancy_AU = A

| routes_of_administration = Oral, intravenous, intramuscular, subcutaneous

| ATC_prefix = R06

| ATC_suffix = AB04

| legal_AU = S3

| legal_UK = P

| legal_US = OTC

| legal_status = CN: OTC

| bioavailability = 25 to 50%

| protein_bound = 72%

| metabolism = Liver (CYP2D6)

| elimination_half-life = 13.9–43.4 hours

| excretion = Kidney

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 132-22-9

| PubChem = 2725

| IUPHAR_ligand = 1210

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB01114

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 2624

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 3U6IO1965U

| KEGG_Ref = {{keggcite|correct|kegg}}

| KEGG = D07398

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 52010

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 505

| IUPAC_name = 3-(4-Chlorophenyl)-N,N-dimethyl-3-(pyridin-2-yl)-propan-1-amine

| C = 16

| H = 19

| Cl = 1

| N = 2

| SMILES = Clc1ccc(cc1)C(c2ncccc2)CCN(C)C

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C16H19ClN2/c1-19(2)12-10-15(16-5-3-4-11-18-16)13-6-8-14(17)9-7-13/h3-9,11,15H,10,12H2,1-2H3

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = SOYKEARSMXGVTM-UHFFFAOYSA-N

| solubility = 0.55 g/100 mL, liquid

}}

Chlorphenamine (CP, CPM), also known as chlorpheniramine, is an antihistamine used to treat the symptoms of allergic conditions such as allergic rhinitis (hay fever). It is taken orally (by mouth).{{cite web |title=Chlorpheniramine |url=https://www.drugs.com/mtm/chlorpheniramine.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |date=26 July 2023 |accessdate=20 August 2023 |language=en |archive-date=20 August 2023 |archive-url=https://web.archive.org/web/20230820022645/https://www.drugs.com/mtm/chlorpheniramine.html |url-status=live }} The medication takes effect within two hours and lasts for about 4–6 hours. It is a first-generation antihistamine and works by blocking the histamine H₁ receptor.

Common side effects include sleepiness, restlessness, and weakness. Other side effects may include dry mouth and wheeziness.

Chlorpheniramine was patented in 1948 and came into medical use in 1949.{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=546 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA546 |language=en}} It is available as a generic medication and over the counter.{{cite web |title=Over-the-Counter Medicines for Allergies |url=https://www.healthlinkbc.ca/health-topics/hw121413 |website=HealthLink BC |access-date=15 July 2019 |language=en |archive-date=15 July 2019 |archive-url=https://web.archive.org/web/20190715162600/https://www.healthlinkbc.ca/health-topics/hw121413 |url-status=dead }}

In 2022, it was the 291st most commonly prescribed medication in the United States, with more than 400,000 prescriptions.{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}{{cite web | title = Chlorpheniramine Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Chlorpheniramine | access-date = 30 August 2024 }}

Medical uses

=Combination products=

Chlorphenamine is often combined with phenylpropanolamine to form an allergy medication with both antihistamine and decongestant properties, although phenylpropanolamine was removed from the U.S. market per studies concluding that it increased the risk of stroke in young women.{{cite press release|url=https://www.fda.gov/cder/drug/infopage/ppa/ |archive-url=https://web.archive.org/web/20090112142816/https://www.fda.gov/cder/drug/infopage/ppa/ |archive-date=12 January 2009 |title=Phenylpropanolamine (PPA) Information Page – FDA moves PPA from OTC |publisher=US Food and Drug Administration |date=23 December 2005}} Vernate was a trade name of one such product available in the U.S. prior to the FDA ban; it was manufactured by Tutag and was among the medications prescribed to Elvis Presley.https://www.jodrugs.com/tradenames/167408-vernate.aspx Information on defunct drug Vernate

In the drug Coricidin, chlorphenamine is combined with the cough suppressant dextromethorphan. In the drug Cêgripe, chlorphenamine is combined with the analgesic paracetamol (also known as acetaminophen, sold as Tylenol).{{Cite web|url=https://www.cegripe.pt/medicamentos-para-a-gripe/cegripe|title=Cêgripe|website=Cegripe.pt|access-date=10 June 2022|archive-date=25 June 2022|archive-url=https://web.archive.org/web/20220625035651/https://www.cegripe.pt/medicamentos-para-a-gripe/cegripe|url-status=live}}

Side effects

The adverse effects include drowsiness, dizziness, confusion, constipation, anxiety, nausea, blurred vision, restlessness, decreased coordination, dry mouth, shallow breathing, hallucinations, irritability, problems with memory or concentration, tinnitus and trouble urinating.

Chlorphenamine produces less sedation than other first-generation antihistamines.{{cite book | vauthors = Landau R, Achilladelis B, Scriabine A | date = 1999 | title = Pharmaceutical Innovation: Revolutionizing Human Health | publisher = Chemical Heritage Foundation | pages = 230–231 | isbn = 978-0-941901-21-5 | url = https://books.google.com/books?id=IH4lPs6S1bMC&pg=PA230}}

A large study on people 65 years old or older linked the development of Alzheimer's disease and other forms of dementia to the "higher cumulative" use of chlorphenamine and other first-generation antihistamines, due to their anticholinergic properties.{{cite journal | vauthors = Gray SL, Anderson ML, Dublin S, Hanlon JT, Hubbard R, Walker R, Yu O, Crane PK, Larson EB | display-authors = 6 | title = Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study | journal = JAMA Internal Medicine | volume = 175 | issue = 3 | pages = 401–407 | date = March 2015 | pmid = 25621434 | pmc = 4358759 | doi = 10.1001/jamainternmed.2014.7663 | author5-link = Rebecca Hubbard }} Chlorphenamine is rated as a "high burden" anticholinergic by experts on a semi-subjective scale.{{cite journal | vauthors = Salahudeen MS, Duffull SB, Nishtala PS | title = Anticholinergic burden quantified by anticholinergic risk scales and adverse outcomes in older people: a systematic review | journal = BMC Geriatrics | volume = 15 | issue = 31 | pages = 31 | date = March 2015 | pmid = 25879993 | pmc = 4377853 | doi = 10.1186/s12877-015-0029-9 | df = dmy-all | doi-access = free }} This is inconsistent with the in vitro experiments showing low affinity to muscarinic acetylcholine receptors (see below).

Pharmacology

=Pharmacodynamics=

Site	K_i (nM)	Species	Ref
class="wikitable floatright" style="font-size:small;" \|+ Chlorphenamine{{cite web \| title = PDSP K_i Database \| work = Psychoactive Drug Screening Program (PDSP) \| author1-link = Bryan Roth \| vauthors = Roth BL, Driscol J \| publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health \| access-date = 14 August 2017 \| url = https://kidbdev.med.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=chlorpheniramine&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query \| archive-date = 2 October 2020 \| archive-url = https://web.archive.org/web/20201002023803/https://kidbdev.med.unc.edu/databases/pdsp.php?knowID=0&kiKey=&receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=chlorpheniramine&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query \| url-status = live }}
{{abbrlink\|SERT\|Serotonin transporter}}	15.2	Human	{{cite journal \| vauthors = Tatsumi M, Groshan K, Blakely RD, Richelson E \| title = Pharmacological profile of antidepressants and related compounds at human monoamine transporters \| journal = European Journal of Pharmacology \| volume = 340 \| issue = 2–3 \| pages = 249–258 \| date = December 1997 \| pmid = 9537821 \| doi = 10.1016/s0014-2999(97)01393-9 }}
{{abbrlink\|NET\|Norepinephrine transporter}}	1,440	Human
{{abbrlink\|DAT\|Dopamine transporter}}	1,060	Human
5-HT_2A	3,130	Rat	{{cite journal \| vauthors = Hoffman BJ, Scheffel U, Lever JR, Karpa MD, Hartig PR \| title = N1-methyl-2-125I-lysergic acid diethylamide, a preferred ligand for in vitro and in vivo characterization of serotonin receptors \| journal = Journal of Neurochemistry \| volume = 48 \| issue = 1 \| pages = 115–124 \| date = January 1987 \| pmid = 3794694 \| doi = 10.1111/j.1471-4159.1987.tb13135.x \| s2cid = 23311638 }}
5-HT_2C	3,120	Rat	{{cite journal \| vauthors = Sanders-Bush E, Breeding M \| title = Putative selective 5-HT-2 antagonists block serotonin 5-HT-1c receptors in the choroid plexus \| journal = The Journal of Pharmacology and Experimental Therapeutics \| volume = 247 \| issue = 1 \| pages = 169–173 \| date = October 1988 \| doi = 10.1016/S0022-3565(25)19989-8 \| pmid = 3139864 }}
H₁	2.5–3.0	Human	{{cite journal \| vauthors = Moguilevsky N, Varsalona F, Noyer M, Gillard M, Guillaume JP, Garcia L, Szpirer C, Szpirer J, Bollen A \| display-authors = 6 \| title = Stable expression of human H1-histamine-receptor cDNA in Chinese hamster ovary cells. Pharmacological characterisation of the protein, tissue distribution of messenger RNA and chromosomal localisation of the gene \| journal = European Journal of Biochemistry \| volume = 224 \| issue = 2 \| pages = 489–495 \| date = September 1994 \| pmid = 7925364 \| doi = 10.1111/j.1432-1033.1994.00489.x \| doi-access = free }}{{cite journal \| vauthors = Arias-Montaño JA, Young JM \| title = Characteristics of histamine H1 receptors on HeLa cells \| journal = European Journal of Pharmacology \| volume = 245 \| issue = 3 \| pages = 291–295 \| date = May 1993 \| pmid = 8335064 \| doi = 10.1016/0922-4106(93)90110-u }}
H₂	{{abbr\|ND\|No data}}	{{abbr\|ND\|No data}}	{{abbr\|ND\|No data}}
H₃	>10,000	Rat	{{cite journal \| vauthors = West RE, Zweig A, Granzow RT, Siegel MI, Egan RW \| title = Biexponential kinetics of (R)-alpha-[3H]methylhistamine binding to the rat brain H3 histamine receptor \| journal = Journal of Neurochemistry \| volume = 55 \| issue = 5 \| pages = 1612–1616 \| date = November 1990 \| pmid = 2213013 \| doi = 10.1111/j.1471-4159.1990.tb04946.x \| s2cid = 83953993 }}
H₄	2,910	Human	{{cite journal \| vauthors = Nguyen T, Shapiro DA, George SR, Setola V, Lee DK, Cheng R, Rauser L, Lee SP, Lynch KR, Roth BL, O'Dowd BF \| display-authors = 6 \| title = Discovery of a novel member of the histamine receptor family \| journal = Molecular Pharmacology \| volume = 59 \| issue = 3 \| pages = 427–433 \| date = March 2001 \| pmid = 11179435 \| doi = 10.1124/mol.59.3.427 \| url = https://cdr.lib.unc.edu/downloads/8336h388z \| access-date = 21 January 2023 \| archive-date = 10 January 2023 \| archive-url = https://web.archive.org/web/20230110194010/https://cdr.lib.unc.edu/downloads/8336h388z \| url-status = live }}
M₁	25,700	Human	{{cite journal \| vauthors = Yasuda SU, Yasuda RP \| title = Affinities of brompheniramine, chlorpheniramine, and terfenadine at the five human muscarinic cholinergic receptor subtypes \| journal = Pharmacotherapy \| volume = 19 \| issue = 4 \| pages = 447–451 \| date = April 1999 \| pmid = 10212017 \| doi = 10.1592/phco.19.6.447.31041 \| s2cid = 39502992 }}
M₂	17,000	Human
M₃	52,500	Human
M₄	77,600	Human
M₅	28,200	Human
{{abbrlink\|hERG\|Human Ether-à-go-go-Related Gene}}	20,900	Human	{{cite journal \| vauthors = Suessbrich H, Waldegger S, Lang F, Busch AE \| title = Blockade of HERG channels expressed in Xenopus oocytes by the histamine receptor antagonists terfenadine and astemizole \| journal = FEBS Letters \| volume = 385 \| issue = 1–2 \| pages = 77–80 \| date = April 1996 \| pmid = 8641472 \| doi = 10.1016/0014-5793(96)00355-9 \| s2cid = 40355762 \| doi-access = free \| bibcode = 1996FEBSL.385...77S }}
class="sortbottom" \| colspan="4" style="width: 1px;" \| Values are K_i, unless otherwise noted. The smaller the value, the more strongly the drug binds to the site. Values at the {{abbrlink\|mAChRs\|muscarinic acetylcholine receptors}} and {{abbrlink\|hERG\|Human Ether-à-go-go-Related Gene}} are IC₅₀ (nM).

Chlorphenamine acts primarily as a potent H₁ antihistamine. It is specifically a potent inverse agonist of the histamine H₁ receptor.{{cite journal | vauthors = Simons FE | title = Advances in H1-antihistamines | journal = The New England Journal of Medicine | volume = 351 | issue = 21 | pages = 2203–2217 | date = November 2004 | pmid = 15548781 | doi = 10.1056/NEJMra033121 }}{{cite journal | vauthors = Leurs R, Church MK, Taglialatela M | title = H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects | journal = Clinical and Experimental Allergy | volume = 32 | issue = 4 | pages = 489–498 | date = April 2002 | pmid = 11972592 | doi = 10.1046/j.0954-7894.2002.01314.x | s2cid = 11849647 }} The drug is also commonly described as possessing weak anticholinergic activity by acting as an antagonist of the muscarinic acetylcholine receptors. The dextrorotatory stereoisomer, dexchlorpheniramine, has been reported to possess K_d values of 15 nM for the H₁ receptor and 1,300 nM for the muscarinic acetylcholine receptors in human brain tissue.{{cite journal | vauthors = Richelson E, Nelson A | title = Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 230 | issue = 1 | pages = 94–102 | date = July 1984 | doi = 10.1016/S0022-3565(25)21446-X | pmid = 6086881 }}{{cite journal | vauthors = Cusack B, Nelson A, Richelson E | title = Binding of antidepressants to human brain receptors: focus on newer generation compounds | journal = Psychopharmacology | volume = 114 | issue = 4 | pages = 559–565 | date = May 1994 | pmid = 7855217 | doi = 10.1007/bf02244985 | s2cid = 21236268 }} The smaller the K_d value, the greater the binding affinity of the ligand for its target.

In addition to acting as an inverse agonist at the H₁ receptor, chlorphenamine has been found to act as a serotonin reuptake inhibitor (K_d = 15.2 nM for the serotonin transporter).{{cite journal | vauthors = Carlsson A, Lindqvist M | title = Central and peripheral monoaminergic membrane-pump blockade by some addictive analgesics and antihistamines | journal = The Journal of Pharmacy and Pharmacology | volume = 21 | issue = 7 | pages = 460–464 | date = July 1969 | pmid = 4390069 | doi = 10.1111/j.2042-7158.1969.tb08287.x | s2cid = 39627573 }} It has only weak affinity for the norepinephrine and dopamine transporters (K_d = 1,440 nM and 1,060 nM, respectively).

A study found that dexchlorphenamine had K_i values for the human cloned H₁ receptor of 2.67 to 4.81 nM while levchlorphenamine had K_i values of 211 to 361 nM for this receptor, indicating that dexchlorphenamine is the active enantiomer.{{cite journal | vauthors = Booth RG, Moniri NH, Bakker RA, Choksi NY, Nix WB, Timmerman H, Leurs R | title = A novel phenylaminotetralin radioligand reveals a subpopulation of histamine H(1) receptors | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 302 | issue = 1 | pages = 328–336 | date = July 2002 | pmid = 12065734 | doi = 10.1124/jpet.302.1.328 | s2cid = 2600032 }} Another study found that dexchlorphenamine had a K_i value of 20 to 30 μM for the muscarinic acetylcholine receptor using rat brain tissue while levchlorphenamine had a K_i value of 40 to 50 μM for this receptor, indicating that both enantiomers have very low affinity for it.{{cite journal | vauthors = Yamamura HI, Snyder SH | title = Muscarinic cholinergic binding in rat brain | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 71 | issue = 5 | pages = 1725–1729 | date = May 1974 | pmid = 4151898 | pmc = 388311 | doi = 10.1073/pnas.71.5.1725 | doi-access = free | bibcode = 1974PNAS...71.1725Y }}

=Pharmacokinetics=

The elimination half-life of chlorphenamine has variously ranged between 13.9 and 43.4 hours in adults following a single dose in clinical studies.{{cite journal | vauthors = Yasuda SU, Wellstein A, Likhari P, Barbey JT, Woosley RL | title = Chlorpheniramine plasma concentration and histamine H1-receptor occupancy | journal = Clinical Pharmacology and Therapeutics | volume = 58 | issue = 2 | pages = 210–220 | date = August 1995 | pmid = 7648771 | doi = 10.1016/0009-9236(95)90199-X | s2cid = 35759573 }}

Chemistry

Chlorphenamine is an alkylamine and is a part of a series of antihistamines including pheniramine (Naphcon) and its halogenated derivatives including fluorpheniramine, dexchlorphenamine (Polaramine), brompheniramine (Dimetapp), dexbrompheniramine (Drixoral), deschlorpheniramine, and iodopheniramine. The halogenated alkylamine antihistamines all exhibit optical isomerism, and chlorphenamine in the indicated products is racemic chlorphenamine maleate, whereas dexchlorphenamine is the dextrorotary stereoisomer.

=Synthesis=

There are several patented methods for the synthesis of chlorphenamine. In one example, 4-chlorophenylacetonitrile is reacted with 2-chloropyridine in the presence of sodium amide to form 4-chlorophenyl(2-pyridyl)acetonitrile. Alkylating this with 2-dimethylaminoethylchloride in the presence of sodium amide gives γ-(4-chlorphenyl)-γ-cyano-N,N-dimethyl-2-pyridinepropanamine, the hydrolysis and decarboxylation of which lead to chlorphenamine.

File:Chlorpheniramine synthesis.png

A second method boom starts from pyridine, which undergoes alkylation by 4-chlorophenylacetonitrile,{{cite journal | vauthors = Djerassi C, Scholz CR | title = Brominations with pyridine hydrobromide perbromide | journal = Journal of the American Chemical Society | volume = 70 | issue = 1 | pages = 417–418 | date = January 1948 | pmid = 18918843 | doi = 10.1021/ja01181a508 | bibcode = 1948JAChS..70..417D }} giving 2-(4-chlorobenzyl)pyridine. Alkylating this with 2-dimethylaminoethylchloride in the presence of sodium amide gives chlorphenamine.

File:Chlorpheniramine synthesis 2.png

Society and culture

= Names =

Chlorphenamine is the {{abbrlink|INN|International Nonproprietary Name}} while chlorpheniramine is the {{abbrlink|USAN|United States Adopted Name}} and former {{abbrlink|BAN|British Approved Name}}.

Brand names include Chlor-Trimeton, Demazin, Allerest 12 Hour, Piriton, Chlorphen-12, Tylenol Cold/Allergy, and numerous others according to country.